Discovery of Gene and Protein Responsible for Cadmium Transport

Daniel W. Nebert, MS, MD
University of Cincinnati Medical Center
R01ES10416 and P30ES06096

Background: Cadmium is a toxic and carcinogenic non-essential metal found in a wide variety of man-made and natural products including cigarette tobacco, shellfish and seafood, soil and plants. Cadmium is readily absorbed through the skin, lungs, and intestines and accumulates in the kidneys. The toxic mechanisms of cadmium are not well understood, but it is known to act intracellularly causing damage to the central nervous system, the lungs, kidneys, and reproductive tissues. Cadmium is also known to cause abnormalities in developing embryos.

Advance: NIEHS-supported researchers at the University of Cincinnati have discovered a gene responsible for the transport of cadmium. The study used low doses of cadmium in mice and demonstrated that the gene, known as Slc39a8, encodes a protein (ZIP8) that transports cadmium to the testes causing vascular endothelial cell injury and leading to testicular tissue death. The testis is a known and sensitive marker of cadmium exposure. Using in vitro models, the research team demonstrated that cells from mice insensitive to cadmium exposure did not have ZIP8, while cells from a strain of cadmium-sensitive mice did contain ZIP8.

Implications: Humans carry the same gene and gene family; therefore, this study has identified a target that could be employed to prevent the toxic effects of cadmium in humans. Cadmium exposure is a significant problem in many Third World countries where undernourishment and iron deficiency are associated with increased cadmium toxicity. The lead researcher on the study, Dr. Dan Nebert, suspects that Slc39a8 could transport cadmium to other regions of the body and may be responsible for the transport of other heavy metals such as lead, nickel, and mercury. He concludes that “Identification and characterization of this gene in mice is a significant breakthrough that will improve our understanding of how heavy metals actually cause toxicity and cancer in humans.”

Citation: Dalton TP, He L, Wang B, Miller ML, Jin L, Stringer KF, Chang X, Baxter CS, Nebert DW. Identification of mouse SLC39A8 as the transporter responsible for cadmium-induced toxicity in the testis. Proc Natl Acad Sci U S A. 2005 Mar 1;102(9):3401-6.